Oxazolo(4,3-a)isoquinolines

ABSTRACT

COMPOUNDS ARE OF THE CLASS OF 1-ARYL-3-AMINO-1,5,6, 10B-TETRAHYDRO-3H-OXAZOLO(4,3-A)ISOQUINOLINES, USEFUL AS CENTRAL NERVOUS SYSTEM STIMULANTS.

United States Patent 3,565,900 OXAZOLO[4,3-a]ISOQUINOL[NES William J.Houlihan and Robert E. Manning, Mountain Lakes, N.J., assignors toSandoz-Wander, Inc., Hanover, N.J., a corporation of Delaware NoDrawing. Continuation-impart of application Ser. No. 663,218, Aug. 25,1967. This application May 21, 1968, Ser. No. 730,957

Int. Cl. C07d 85/48 US. Cl. 260-286 15 Claims ABSTRACT OF THE DISCLOSURECompounds are of the class of l-aryl-3-amino-l,5,6,l0b-tetrahydro-3H-oxazolo[4,3-a1isoquinolines, useful as central nervoussystem stimulants.

This application is a continuation-in-part of application Ser. No.663,218 filed Aug. 25, 1967, now abandoned.

This invention relates to tricyclic compounds. In particular, theinvention pertains to 1-aryl-3-imino-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a1isoquinolines, acid addition saltsthereof, and to processes for preparing the same. The invention alsorelates to intermediates which are useful in preparing the abovecompounds and to processes for preparing said intermediates.

The oxazolo[4,3-a]isoquinolines of the present invention may berepresented structurally as follows:

wherein R, R R and R independently, represent hydrogen trifluoromethyl,or halo having an atomic weight of about 19-36;

R and R independently, represent hydrogen, straight chain lower alkyl,or halo having an atomic weight of about 19-36; and

R represents hydrogen or straight chain lower alkyl,

provided (1) no more than three of R, R R R R and R are other thanhydrogen, and (2) 'R, R R and R are such that there is never atrifluoromethyl group on each of two adjacent carbon atoms, and A is amonovalent anion.

This invention also includes within its scope the free base of thecompounds of Formula I where R is hydrogen.

The term lower alkyl signifies an alkyl group having 1-4 carbon atoms,viz., methyl, ethyl, propyl and butyl.

The compounds of Formula I wherein R through R are halo as defined aboverepresent a preferred aspect of this invention. Particularly preferredare those compounds where either R or R and 'R represent chloro.

The compounds of Formula I are conveniently prepared by reacting anappropriate a-aryl-1,2,3,4-tetrahydroisoquinoline-l-methanol (III) withcyanogen bromide. Alternatively, the compounds may be prepared byreacting an appropriatel-(a-hydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline-Z-carboxamicle (II)with thionyl chloride.

3,565,900 Patented Feb. 23, 1971 ice These processes are illustrated bythe following reaction scheme:

wherein R through R and A are as previously defined. The reaction of thecarboxamide (II) with thionyl chloride is carried out in an intertorganic solvent, preferably a chlorinated low molecular weighthydrocarbon, e.g., methylene chloride, chloroform and carbontetrachloride, and at an elevated temperature of from about 35 C. toabout C. Preferably, the reaction is carried out at a temperature offrom about 40 C. to about 50 C.

Conversion of the carbinol (III) to the desired comfound of Formula I byuse of cyanogen bromide is readily carried out in an inert organicsolvent and at a temperature of from about 0 C. to about 20 C.Preferably, the reaction is carried out at a temperature of from about 5C. to about 10 C. employing a lower aliphatic alcohol, e.g., methanol,ethanol and isopropanol, as the solvent. When R is straight chain loweralkyl, an intermediate tautomeric form of the free base of the compoundsof Formula I is formed having the structure where R-R are as previouslydefined, and such compounds are readily converted to the compounds ofFormula I where R is straight chain lower alkyl by treatment with acid,e.g., hydrochloric and hydrobromic acid, or sulphuric, phosphoric acid,and the like, conveniently at a. temperature of from about 0 C. to about40 C., preferably about room temperature. Use of solvent is notnecessary.

In each of the above processes, the product obtained is readily isolatedemploying conventional techniques.

The free base of the compounds of Formula I are believed to existessentially only when R is hydrogen, and

such compounds may be obtained by treating compounds (I) with a base inconventional manner.

The compounds of Formula II are readily obtained from the correspondingcompounds of Formula III by treatment of the latter, under acidicconditions, with an alkali-metal isocyanate, preferably potassiumisocyanate, in an inert organic solvent, preferably a lower aliphaticalcohol, e.g., methanol, ethanol and isopropanol. The reaction ispreferably carried out in the presence of a mineral acid, e.g.,hydrochloric acid, sulphuric acid and phosphoric acid, and at atemperature of from about C. to about C. However, the reaction can beeffected at a temperature of from about 0 C. to about C. and in thepresence of any suitable inert inorganic or organic acid which iscapable of liberating cyanic acid, e.g., ptoluenesulfonic acid andacetic acid.

Various of the compounds of Formula III are known and can be prepared asdescribed in the literature. Such others which may, not be specificallydisclosed in the literature may be prepared from available materials ina manner analogous to that described in the literature for preparing theknown compounds. In general, such compounds are prepared by reacting1-cyano-2-benzoyl- 1,2-dihydroisoquinoline (prepared by the procedure ofI. Weinstock and V. Boekelheide in Organic Synthesis, Coll. Vol. 2, p.641) with an appropriate lithium compound to form the correspondingl-lithio derivative, treating the latter with benzaldehyde (orappropriate derivative thereof) to form the correspondinga-aryl-isoquinoline-l-methanol and catalytically hydrogenating thelatter, e.g., in acetic acid in the presence of a platinum catalyst andat a temperature of from 25 C. to C. and a hydrogen pressure of 1 to 5atmospheres.

The compounds of Formula III are alternatively prepared from N-(substituted phenethyl)-2-phenyl acetamides (V) according to thefollowing reaction scheme it v) it (VI) where R-R are as earlierdefined. These carbinol intermediates (III) are prepared by cyclizingsaid acetamides (V) with phosphorous pentoxide in solvent such asbenzene or xylene at about 75 C. to 150 C. to obtain a correspondingl-benzyl dihydroisoquinoline (VI), treating said dihydroisoquinolinewith air or oxygen, con veniently at room temperature, to obtain acorresponding l-benzoyl dihydroisoquinoline (VII) and reducing thiscompound (VII) at a temperature of 20 C. to C. in solvent, e.g.,ethanol, with hydrogen in the presence of platinum as catalyst. Certainof the acetamide starting materials (V) are known and are preparedaccording to methods disclosed in the literature. Those acetamides notspecifically disclosed may be prepared by analogous methods from knownmaterials.

The compounds of Formula I exist as geometric isomers. Each of theabove-described processes for preparing (I) results in the production ofcompounds of a particular geometric isomer configuration. For thepurpose of this invention, the compounds (I) obtained via the reactionof the carbinols (III) where R is hydrogen with cyanogen bromide aredesignated as Isomer A while the compounds resulting from the reactionof a carboxamide (II) where R is hydrogen with thionyl chloride aredesignated as Isomer B. Likewise, reaction of the carbinols defined byFormula III where R is lower alkyl with cyanogen bromide providescompounds (I) referred to herein as Isomer C whereas the compoundsresulting from the reaction of thionyl chloride with a carboxamide (II)where R is lower alkyl may be designated as Isomer D. The compounds ofFormula I in all geometric isomer forms also exist as optical isomers,and the separation and recovery of the respective isomers may be readilyaccomplished employing conventional techniques. All of the isomers(geometric and optical) are included within the scope of this invention.

All of the compounds of Formula I are useful because they possesspharmacological activities in animals. In particular, the compoundspossess central nervous system activity and can be used asantidepressants as indicated by their activity in the mouse given 10nag/kg. intraperitoneally of the active compound and tested for itsability to reverse reserpine hypothermia (Spencer, P.S.J., Antagonism ofHypothermia in the Mouse by Antidepressants, in Antidepressant Drugs,pp. 194204, Eds., S. Garattini and M.N.G. Dukes, Excerpta MedicaFoundation, 1967).

Compounds (1) and particularly those defined as Isomer B are also usefulas anorexics as indicated by their activity in rats orally given 25mg./kg. of active compound and tested using the free feeding methoddescribed by Randall et al. (J.P.E.T., 129:163, 1960).

For such uses, the compounds may be combined with a pharmaceuticallyacceptable carrier, and such other conventional adjuvants, as may benecessary, and administered orally in such forms as tablets, capsules,elixirs, suspensions or solutions, or parenterally in such forms asinjeetable solutions, suspensions or emulsions. The com pounds may beadministered in the form of their nontoxic, pharmaceutically acceptableacid addition salts or in free base form when R is hydrogen. The saltspossess the same order of activity as said free base. The free base formof the compounds of Formula I, Whether it exists as anoxazolo[4,3-a]isoquinoline or a carbonitrile (Ia), is readily preparedfrom the salts (I) using conventional techniques. The pharmaceuticallyacceptable salts are likewise readily prepared in conventional manner byreacting the base of the compounds of Formula I or the tautomericintermediate (Ia) with the appropriate acid. Representative of suchsalts are the mineral acid salts such as hydrochloride, hydrobromide,sulfate, phosphate and the like and the organic acid salts such as thesuccinate, benzoate, acetate, maleate, p-toluenesulfonate and the like.

The dosage administered Will, of course, vary depending on theparticular compound employed and mode of administration. However, ingeneral, satisfactory results are obtained when the compounds areadministered for the anti-depressant use at a daily dosage of from about10-3O mg./kg. of animal body weight, preferably given in divided doses,e.g., 2 to 4 times a day or in sustained release form. For most largemammals the total daily dosage is in the range of from about 20 mg. toabout mg. Suitable dosage forms comprise from about 5 mg. to about 50mg. admixed with a pharmaceutically acceptable carrier or diluent.

When the compounds are to be utilized an anorexics, satisfactory resultsare obtained when the compounds are administered at a daily dosage offrom about mg. to about 30 mg./kg. of animal body weight, preferablygiven in divided doses, e.g., 2 to 4 times a day or in sustained releaseform. For most large mammals the total daily dosage for this use is fromabout 20 mg. to about 100 mg. and suitable dosage forms comprise fromabout 5 mg. to about 50 mg. admixed with a pharmaceutically acceptablecarrier or diluent.

A representative formulation suitable for oral administration is atablet prepared by standard tabletting techniques and containing thefollowing:

Ingredient Parts by weight 1(p-chlorophenyl)-3-imino-l,5,6,10b-tetrahydro- 3H oxazolo[4,3a]isoquinoline hydrochloride(Isomer A or B) 25 Tragacanth 2 Lactose 64.5Corn starch 5 Talcum 3 Magnesium stearate 0.5

The following examples show representative compounds contemplated bythis invention and the manner in which such compounds are prepared.However, it is to be understood that these examples are intended forpurposes of illustration only and are not intended as in any waylimiting the scope of the invention which is defined in the appendedclaims.

EXAMPLE 1 1- (p-chlorophenyl)-3-imino-1,5,610b-tetrahydro-3H- oxazolo[4, 3-a] isoquinoline (Step A) Preparation ofa-(p-chlorophenyl)-isoquino line-1-methanol.-To a flask equipped with athermometer, condenser, dropping funnel, gas inlet tube and stirrer isadded 500 ml. of absolute tetrahydrofuran and 26.0 g. (0.10 mole) of1-cyano-2-banzoyl-1,2-dihydroisoquinoline. The system is blanketed withnitrogen and the solution cooled in an ice-salt-methanol bath to aninternal temperature of C. To the cooled solution is then added,dropwise over a period of 15 minutes, 50 ml. of a 2 M solution ofphenyllithium in tetrahydrofuran. To the resulting solution is added,with stirring, a solution of 14.1 g. (0.10 mole) of p-chlorobenzaldehydein 75 ml. of tetrahydrofuran at such a rate that the internaltemperature does not exceed -10 C. After the addition is completed thesolution is stirred for an additional hour at -10 C. and then allowed tostand at room temperature C.) for 12 hours. To the solution is thenadded 500 ml. of tetrahydrofuran and the resulting solution extractedfirst with ml. of water, then with 30 ml. of 0.5 N hydrochloric acid andthen again with 30 ml. of water. The tetrahydrofuran is then removed invacuo and the residue [benzoate salt ofix-(p-chlorophenyl)-isoquinoline-l-methanol] dissolved in 500 ml. of 95%ethanol. To the resulting solution is added 16.2 g. (0.29 mole) ofpotassium hydroxide in 125 ml. of water. The resulting mixture isrefluxed for 16 hours and then concentrated in vacuo. To the residue isadded 100 ml. of water and the resulting solution extracted with 200 ml.of toluene. The toluene extract is dried over anhydrous magnesiumsulfate and the toluene then removed in vacuo to obtain a-(p-ChlOlO-phenyl)-isoquinoline-l-methanol, M.P. 98103 C.

When the above procedure designated Step A is carried out andm-trifluoromethyl benzaldehyde, p-fluorobenzaldehyde or3,4-dichlorobenzaldehyde is used in place of pchlorobenzaldehyde, thereis obtained ot-(m-trifluoromethylphenyl)-isoquinoline-1-methanol (M.P.97-99 C. a-(p-fiuorophenyl) -isoquinolinel-methanol (M.P. -87 C.), ora-(3,4-dichlorophenyl)-isoquinoline-1- methanol (M.P. 114-1l6 C.),respectively.

(Step B) Preparation of a-(p-chlorophenyl)-l,2,3,4tetrahydroisoquinoline-1-methanol.-A mixture of 14.0 g. (0.052 mole) ofa-(p-chlorophenyl)-isoquinoline-1-methanol, ml. of acetic acid and 0.5g. of platinum dioxide (in a Paar hydrogenation bottle) is hydrogenatedat 45 p.s.i. and room temperature until the hydrogen uptake is complete(3 equivalents hydrogen; 3 hours). The catalyst is then filtered off andthe filtrate concentrated in vacuo. To the resulting oily residue isadded 75 ml. of 2 N sodium hydroxide and the resulting mixture extractedwith ml. of chloroform. The chloroform extract is dried over anhydrousmagnesium sulfate and then concentrated in vacuo. The resulting residueis crystallized from pentane to obtaina-(p-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-l-methanol, M.P. 97101C.

When the procedure of Step B is used anda-(m-trifiuoromethylphenyl)-isoquinoline 1 methanol, a-(pfluorophenyl-isoquinoline- 1 -methanol, or a- 3,4-dichlorophenyl)-isoquinoline-l-methanol is used in place ofOt-(pchlorophenyl)-isoquinoline-l-methanol, there is obtainedu-(m-trifiuoromethylphenyl) 1,2,3,4 tetrahydroisoquinoline-l-methanol(M.P. 97.599.5), a-(p-fiuorophenyD-1,2,3,4-tetrahydroisoquinoline-l-methanol (M.P. 7378 C. ora-(3,4-dichlorophenyl) -1,2,3,4-tetrahydroisoquinoline-l-methanol (M.P.89-99 C.), respectively.

(Step C) Preparation of l-(p-chlorophenyl)-3-iminol,5,6,l0b-tetrahydro3H oxazolo[4,3-a]isoquinoline.-- A solution of 7.3 g. (0.027 mole) ofu-(p-chlorophenyD- 1,2,3,4-tetrahydroisoquinoline-1-methanol, 4.4 g.(0.0534 mole) of sodium acetate and 125 ml. of methanol is cooled toabout 5 C. To the cooled solution is added, dropwise, a solution of 2.8g. (0.0267 mole) of cyanogen bromide in 15 m1. of methanol. Afterstirring for 12 hours at room temperature (2025 C.) the solvent isevaporated and the residue dissolved in water. To the resulting solutionis added 2 N sodium hydroxide until basic (pH 10). The resulting oil isextracted with 75 ml. of methylene chloride, the methylene chlorideextract dried over anhydrous magnesium sulfate and then concentrated invacuo to obtain 1 (p-chlorophenyl)-3-imino-1,5,6,IOb-tetrahydro-3H-oxazolo[4,3-a]isoquinoline as an oil (Isomer A).

The oily base is dissolved in tetrahydrofuran, the re sulting solutiontreated with hydrogen chloride gas and precipitated salt recovered byfiltration to obtain l-(pchlorophenyl)-3-imino-1,5,6,10b-tetrahydro 3Hoxabolo[4,3-a]isoquino1ine hydrochloride, M.P. -168 C. (Isomer A). Whenthe above oily base dissolved in tetrahydrofuran is treated with maleicacid, there is obtained l-(p-chlorophenyl)-3-imino 1,5,6,10btetrahydro-BH- oxazolo[4,3-a]isoquinoline maleate; M.P. 168169 C.(Isomer A).

When the above procedure designated Step C is repeated anda-(m-trifluoromethylphenyl)-1,2,3,4-tetrahydroisoquinoline 1 methanol,a- (p-fluorophenyl)-1,2,3,4- tetrahydroisoquinoline 1 methanol, or(it-(3,4-diCh10l'O phenyl)-1,2,3,4-tetrahydroisoquinoline 1 methanol isused in place ofot-(p-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-l-methanol, there isobtained l-(m-trifluoromethylphenyl)-3-imino-1,5,6,10btetrahydro 3Hoxazolo[4,3-a]isoquinoline hydrochloride (M.P. 186-190 C.) (Isomer A),l-(p-fluorophenyl)-3-imino-1,5,6,10btetrahydro-3H-oxazolo[4,3a]isoquinoline hydrochloride (M.P. 227230 C.) (Isomer A), or1-(3,4-dichlorophenyl) 3 imino-1,5,6,l0b-tetrahydro-3H-oxazolo[4,3-a]isoquinoline hydrochloride (M.P. 168170 C.) (Isomer A), respectively.

Likewise, when the above procedure designated Step C is used and7-methyl-a-phenyl-1,2,3,4-tetrahydroisoquinoline-l-methanol,7-chloro-a-phenyl-1,2,3,4 tetrahydroiso- .quinoline-l-methanol, or7-fluoro-tx-phenyl-l,2,3,4-tetrahydroisoquinoline-l-methanol is used inplace of a-(p-chlorophenyl) l,2,3,4 tetrahydroisoquinoline l methanol,.there is obtained 1 phenyl-3-imino-9-methyl-l,5,6,10b-

tetrahydro 3H-oxazolo[4,3-alisoquinoline hydrochloride (M.P. 267269 C.)(Isomer A), 1-phenyl-3-imino-9- chloro 1,5,6,10b tetrahydro 3Hoxazolo[4,3-a]isoquinoline hydrochloride (M.P. 261-262 C.) (Isomer A),or 1-phenyl-3-imino-9-fluoro-1,5,6,l0b-tetrahydro-3H-oxazolo[4,3-a]isoquinoline hydrochloride (M.P. 258 259 C.) (Isomer A),respectively.

EXAMPLE 2 l-(p-chlorophenyl) -3imino-1,5,6,10b-tetrahydro-3 H-oxa-Zol[4,3-a] isoquinoline hydrochloride (Alternate process) (Step A)Preparation of 1-(p-chloro-a-hydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline-Z-carboxamide.To a solution of 5.6 g. ofa-(p-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline -1-methanol in 12 ml.of methanol and 3.5

ml. of concentrated hydrochloric acid is added a solution of 1.8 g. ofpotassium isocyanate in 4 ml. of water. The resulting mixture is stirredovernight (16 hours) at room temperature (2025 C.) and the resultingsolid mass diluted with ml. of methanol and 10 ml. of water and thenrecovered by filtration to obtain l-(p-chloro-a-hydroxybenzyl) 1,2,3,4tetrahydroisoquinoline 2 carboxamide, M.P. 67-69 C.

(Step B) Preparation of 1-(p-chlorophenyl)-3-imino- 1,5,6,10b tetrahydro3H oxazolo[4,3-a]isoquinoline hydrochloride.To a cooled solution (icebath) of 12.5

g. of1-(pchloro-a-hydroxybenzyl)-l,2,3,4-tetrahydroisoquinoline-Z-carboxamidein 100 ml. of methylene chloride is added, with stirring, a solution of5.0 g. of thionyl chloride in 40 ml. of methylene chloride. Theresulting solution is refluxed for 30 minutes and then evaporated invacuo. The residue is heated with 100 ml. of water on a steam bath for30 minutes, then cooled and the resulting solid material recovered byfiltration and crystallized from methylene chloride-acetone (1:1) toobtain 1-(p-chlorophenyl) 3-imino 1,5,6,10b tetrahydro 3H oxazolo[4,3-a]is0quinoline hydrochloride, M.P. 239240 C. (dec.) (Isomer B).

When the procedure of Steps A and B immediately above are used andot-(m-trifluoromethylphenyl)-1,2,3,4- tetrahydroisoquinoline l methanol,a-(p-fiuorophenyh- 1,2,3,4 tetrahydroisoquinoline 1 methanol, orOt-(3,4- dichlorophenyl) 1,2,3,4 tetrahydroisoquinoline 1 methanol isused in place of a-(p-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-l-methanol, there is obtained 1-(m-trifluoromethylphenyl) 3 imino 1,5,6,10b tetrahydro 3Hoxazolo[4,3-a]isoquinoline hydrochloride (M.P. 244-245 C.) (Isomer B),l-(p-fluorophenyl)-3- imino 1,5,6,10b tetrahydro 3Hoxazolo[4,3-a]isoquinoline hydrochloride (M.P. 209-211 C.) (Isomer B),or1-(3,4-dichlorophenyl)-3-imino-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a]isoquinolinehydrochloride (M.P. 219-221 C.) (Isomer B), respectively.

EXAMPLE 3 1-phenyl-3-imino-1,5,6,10b-tetrahydro-3H-oxazolo [4,3-a]isoquinoline N\ NH f A solution of 12.5 g. (0.052 mole) ofa-phenyl-l,2,3,4 tetrahydroisoquinoline-1-methanol, 8.5 g. (0.104 mole)of sodium acetate and 100 ml. of methanol is cooled to about 5 C. To thecooled solution is added, dropwise, a solution of 5.5 g. (0.052 mole) ofcyanogen bromide in 25 ml. of methanol. After stirring for 12 hours atroom temperature (2025 C.) the solvent is evaporated and the residuedissolved in water. To the resulting solution is added 2 N sodiumhydroxide until basic (pH 10). The resulting oil is extracted with 100ml. of methylene chloride, the methylene chloride extract dried overanhydrous magnesium sulfate and then concentrated in vacuo to obtain1-phenyl-3-imino-1,5,6,10b-tetrahydro-3H-oxazolo [4,3-a1isoquinoline asan oil (Isomer A).

The oily base is dissolved in tetrahydrofuran, the resulting solutiontreated with hydrogen chloride gas and the precipitated salt recoveredby filtration to obtain 1- phenyl 3 imino-1,5,6,10b-tetrahydro 3 H-oxazolo [4,3-a]isoquinoline hydrochloride, M.P. 228-230 C. (Isomer A).

EXAMPLE 4 1- (2,4-dichlorophenyl -3-imino- 1 ,5,6, 1 0b-tetrahydro-3H-oxazolo [4,3-a] isoquinoline 0 Cl -Cl (Step A) Preparation of oc-(2,4dichlorophenyl) isoquinoline-1-methanol.To a flask equipped with athermometer, condenser, dropping funnel, gas inlet tube and stirrer isadded 650 ml. of absolute tetrahydrofuran and g. (0.25 mole) of1-cyano-2-benzoyl-1,2-dihydroisoquinoline. The system is blanketed withnitrogen and the solution cooled in an ice-salt-rnethanol bath to aninternal temperature of -15 C. To the cooled solution is then added,dropwise over a period of 15 minutes, 125 ml. (0.25 mole) of 2.14 molarphenyllithium is tetrahydrofuran. To the resulting solution is added,with stirring, a solution of 43.8 g. (0.25 mole) of2,4-dichlorobenzaldehyde in 300 ml. of tetrahydrofuran at such a ratethat the internal temperature does not exceed 10 C. After the additionis completed the solution is stirred for an additional hour at l0 C. andthen allowed to stand at room temperature (20 25 C.) for 12 hours. Tothe solution is then added 500 ml. of tetrahydrofuran and the resultingsolution extracted first with ml. of Water, then with 7-5 ml. of 0.5 Nhydrochloric acid and then again with 75 ml. of Water. Thetetrahydrofuran is then removed in vacuo and the residue dissolved in1000 ml. of ethanol. To the resulting solution is added 40.5 g. (0.725mole) of potassium hydroxide in 250 ml. of water. The resulting mixtureis refluxed for 16 hours and then concentrated in vacuo. To the residueis added 250 ml. of Water and the resulting solution extracted threetimes each With 200 ml. of toluene. The toluene extract is dried oversodium sulfate, the toluene then removed in vacuo and the residuecrystallized from ether-pentane (1:1) to obtain a-(2,4dichlorophenyl)-isoquinoline 1 methanol, M.P. 97-100 C.

(Step B) Preparation of tx-(2,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-1-methanol.A mixture of 40.9 g. (0.135 mole) ofa-(3,4-dichlorophenyl)-isoquinoline-1- methanol, 125 ml. of acetic acidand 1.0 g. of platinum dioxide (in a Paar hydrogenation bottle) ishydrogenated at 49 p.s.i. and room temperature until the hydrogen uptakeis complete (4 hours). The catalyst is then filtered off and thefiltrate concentrated in vacuo. To the resulting oily residue is added100 ml. of 2 N sodium hydroxide and the resulting mixture extracted with250 ml. of chloroform. The chloroform extract is dried over anhydroussodium sulfate and then concentrated in vacuo.

The resulting residue is crystallized from pentane-ether (1:1) to obtaina-(2,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquino-line-1-methanol, M.P.132134 C.

(Step C) Preparation of 1-(2,4-dichlorophenyl)-3 imino1,5,6,10b-tetrahydro 3H-oxazolo[4,3-a]insoquinoline.A solution of 20.0g. (0.065 mole) of a-(2,4-dichlorophenyl) 1,2,3,4-tetrahydroisoquinoline1-meth anol, 10.7 g. (0.13 mole) of sodium acetate and 500 ml. ofmethanol is coo-led to about C. To the cooled solution is added,dropwise, a solution of 6.8 g. (0.065 mole) of cyanogen bromide in 50ml. of methanol. After stirring for hours at room temperature (25 C.)the solvent is evaporated and the residue dissolved in water. To theresulting solution is added 2 N sodium hydroxide until basic (pH 10).The resulting oil is extracted with 150 ml. of methylene chloride, themethylene chloride extract dried over anhydrous magnesium sulfate andthen concentrated in vacuo to obtain 1-(2,4-dichlorophenyl)-3- imino1,5,6,10b-tetrahydro 3H-oxazolo[4,3-a]isoquinoline as an oil (Isomer A).

The oily base is dissolved in tetrahydrofuran, the resulting solutiontreated with hydrogen chloride gas and precipitated salt recovered byfiltration to obtain 1-(2,4-dichlorophenyl)-3-imino1,5,6,10b-tetrahydro-ElH-oxazolo [4,3-a]isoquinoline hydrochloride, M.P.170176 C. (Isomer A).

EXAMPLE 5 1-(2,4-dichlorophenyl) 3-imino 1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a]isoquinoline hydrochloride (Alternate process) (Step A)Preparation of 1-(2,4-diChlOIO-ot-hYdFOXY-benzyl)-1,2,3,4-tetrahydroisoquinoline 2-carboxamide. To a solution of7.2 .g. (0.021 mole) ofa-(2,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline l-methanol in 50ml. of methanol, 200 ml. of water, and 2.2 ml. of concentratedhydrochloric acid is added a solution of 2.0 g. of potassium isocyanatein 10 ml. of water. The resulting mixture is stirred for 48 hours atroom temperature (20-25 C.) and the resulting solid mass recovered byfiltration to obtain 1-(2,4-dichloro-a-hydroxybenzyl)-1,2,3,4tetrahydroisoquinoline-2-carboxamide.

(Step B) Preparation of 1-(2,4-dichlorophenyl)-3imino-1,5,6,10b-tetrahydro 3H-oxazolo[4,3-a]isoquinolinehydrochloride.-To a cooled solution (ice bath) of 6.2 g. (0.018 mole) of1-(2,4-dichloro-a-hydroxybenzyl)- 1,2,3,4-tetrahydroisoquinoline2-carboxamide in 150 ml. of methylene chloride is added, with stirring,a solution of 2.2 g. of thionyl chloride in 10 ml. of methylenechloride. The resulting solution is refluxed for minutes and thenevaporated in vacuo. The residue is heated with 50 ml. of Water on asteam bath for 30 minutes, then cooled and the resulting solid materialrecovered to obtain 1-(2,4-dichloro-phenyl) 3-imino1,5,6,10b-tetrahydro- 3H-oxazolo[4,3-a]isoquinoline hydrochloride, M.P.196- 199 C. (Isomer B.)

EXAMPLE 6 1-phenyl-3-irnino-5-methyl-1,5,6,10b-tetrahydro-3H- oxazolo[4,3-a]isoquinoline hydrochloride (Step A) 2-benzoyl1,2-dihydro3-methylisoquinoline- 1-carbonitrile.In a 3-liter four-neck flask,equipped with mechanical stirrer, dropping funnel, thermometer andcondenser are placed a solution of 196 g. of potassium cyanide in 1250ml. of water and 143 g. of 3-methylisoquinoline. While the temperaturewas maintained between 5 and 10 by use of an ice bath, 281 g. ofbenzoylchloride is added dropwise for 2 hours. After another 1.5 hours,the resulting material crystallizes and is filtered off, washed Withwater (200 ml.), 2 N HCl solution (300 ml.) and water (300 ml.). Thecrude material (330 g.) is recrystallized from ethanol three times toafford 2-benzoyl-1,2- dihydro-3-methylisoquinoline l-carbonitrile; M.P.137 138 C.

(Step B) a-phenyl 3-methyl 1,2,3,4-tetrahydroisoquinoline I-methanolhydrochloride.-2-benzoyl 1,2- dihydro 3-methylisoquinoline (27.4 g.) isdissolved in 500 ml. of absolute tetrahydrofuran in a 2-liter four-neckflask equipped with thermometer, dropping funnel, condenser Withnitrogen inlet and mechanical stirrer. The internal temperature ismaintained between 20 C. and 10 C. A 2 molar solution ml.) ofphenyllithium in benzene/ether (:30) is added dropwise. To the resultantred solution, 10.6 g. of benzaldehyde in ml. absolute tetrahydrofuran isadded dropwise over a 20- minute period. The mixture is stirred for onehour at 10 C., then at room temperature overnight. After work up 38 g.of an oil is obtained which is hydrolized in 100 ml. of 2 N potassiumhydroxide and 500 ml. of ethanol by refluxing overnight. The mixture isconcentrated in vacuo to about 200 ml. and worked up to provide 28 g. ofan oil which is hydrogenated without further purification in ml. ofglacial acetic acid in the presence of 250 mg. of platinum dioxide.After the absorption of hydrogen has stopped, the catalyst is removed byfiltration and the solution is evaporated in vacuo. Ether ml.) is addedand the product is precipitated as hydrochloride by adding 100 ml. of 2N HCl solution. Crude product (16.2 g.) is filtered off andrecrystallized from ethanol/ ether to yield 13.8 g. of u-phenyl-3-methyl1,2,3,4-tetrahydroiscquinoline-l-methanol hydrochloride; M.P. 198- 199C.

When the procedure of Steps A and B above are repeated andp-chlorobenzoylchloride or 3,4dichlorobenzoylchloride is used in placeof benzoylchloride, there is obtained u(-p-chlorophenyl) 3-methyl1,2,3,4-tetrahydroisoquinoline l-methanol hydrochloride; (M.P. 213 C.),or a-(3,4-dichlorophenyl) 3-methyl 1,2,3,4-tetrahydroisoquinolinel-methanol hydrochloride; (M.P. 230- 233 C.), respectively.

(Step C) l-(a-hydroxybenzyl) -3-methyll,2,3,4-tetrahydroisoquino1ine-2-carbonitrile.a-Phenyl-3 methyl-1,2,3,4-tetrahydroisoquinoline 1-methano1 HCl (4.5 g.) is dissolved in 100 ml.of warm water. 10 ml. of 2 N sodium hydroxide solution andmethylenechloride are added and Work up yields 3.2 g. ofa-phenyl-3-methyl-1,2,3,4-tetrahydroisoquinoline-l-methanol; M.P. 9698C. To 2.53 g. of the above free base dissolved in 70 ml. of absolutemethanol is added 1 g. of anhydrous sodium acetate. To this ice coldsolution is added, dropwise, 1.1 g. of cyanogen bromide in 30 ml. ofabsolute methanol. After 2 hours at room temperature, methanol isevaporated in vacuo. Extraction with methylene chloride affords 3.8 g.of crude product; M.P. 141 C. After recrystallization from methylenechloride/hexane 2.5 g. of pure l-(a-hydroxybenzyl)-3-methyl1,2,3,4-tetrahydroisoquinoline-2- carbonitrile is obtained; (M.P. 144145C.).

When the above process is carried out and nt-(P-ChlOI'O-phenyl)-3-methyl-1,2,3,4 tetrahydroisoquinoline-l-methauol ora-(3,4-dichlorophenyl)-3-methyl-l,2,3,4-tetrahydroisoquinoline-1-methanol is used in place of a-phenyl-3-methyl-1,2,3,4-tetrahydroisoquinoline-l-methanol, there is obtained1-(p-chloro-a-hydroxybenzyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-Z-carbonitrile (M.P. 151 C.) or1-(3,4-dichloro-a-hydroxybenzyl)-3-methy1-1,2,3,4-tetrahydroisoquinoline-2-carbonitrile(M.P. 147149 C.), respectively.

(Step D)1-phenyl-3-imino-5-methyl-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a1isoquinolinehydrochloride.-1-(ahydroxybenzyl)-3-methy1-1,2,3,4tetrahydroisoquinoline- 2-carbonitrile (1.5 g.) is cyclized at 25 C.with ml. of MCI in ethanol. The hycrochloride precipitates and isfiltered to provide 1.8 g. of crude material; M.P. 252 C. Tworecrystallization from ethanol/ether (1:1) provides1-phenyl-3-imino-S-methyl-1,5,6,10b-tetrahydro-3H- oxazolo[4,3a]isoquinoline hydrochloride; M.P. 267- 268 C.

When the process of Step D is repeated and l-(p-chloroot-hydroxybenzyl)-3-methyl-1,2,3,4 tetrahydroisoquinoline-2-car bonitrile or1-(3,4-dichloro-ot-hydroxybenzyl)-3- methyl-1,2,3,4tetrahydroisoquinoline-2-carbonitrile is used in place ofl-(whydroxybenzyl)-3-methyl-1,2,3,4tetrahydroisoquinoline-2-carbonitrile, and when in the case of thep-chloro compound HBr is used in place of HCl, there is obtained1-p-chlorophenyl-3-imino-5-methyl-1,5, 6,10b-tetrahydro3H-oxazolo[4,3-a]isoquinoline hydrobromide (M.P. 237238 C.) or1-(3,4-dichlorophenyl)- 3-imino-5-methyl1,5,6,10b-tetrahydro-3H-oxazolo[4,3- ot]isoquinoline hydrochloride (M.P.246247 C.), respectively.

EXAMPLE 7 7-ch1oro-ot-phenyl-1,2,3,4-tetrahydroisoquinolinel-methanol(Step A) 1-benzyl-7-chloro-3,4-dihydroisoquinoline.-N-(p-chlorophenethyl)-2-phenyl acetamide (57 g.) is re fluxed overnightin 500 ml. of Xylene in the presence of 120 g. of phosphorous pentoxideand 80 g. of pumice. The xylene layer is decanted and the residuedissolved in water, ice and concentrated HCl. The pumice is filtered offand the aqueous solution extracted with dichloromethane. The organicphase is discarded and the aqueous part is made basic (pH 10) with 50%NaOH and extracted 3 times with dichloromethane. The solvent isevaporated providing 23 g. of crude 1-benzyl-7-chloro-3,4dihydroisoquinoline.

(Step B) 1-benzoyl-7-chloro-3,4-dihydroisoquinoline.- A solution of1-benzyl-7-chloro'3,4-dihydroisoquinoline (22 g.) in 500 ml. of benzeneis treated by bubbling air through the solution, and evaporating it todryness, to obtain 6.2 g. of brown oil. After purification on silicagel, 550 mg. of crystalline 1-benzoyl-7-chloro-3,4-dihydroisoquinolineis obtained (M.P. 9899 C.).

(Step C)7-chloro-wphenyl-1,2,3,4-tetrahydroisoquinoline-1-methanol.1-benzoyl 7chloro-3,4-dihydroisoquinoline (2.0 g.) dissolved in 50 ml. of absoluteethanol is hydrogenated at about 40 p.s.i. in the presence of 500 mg. ofplatinum dioxide. After one-half hour, hydrogen absorption ceases, thecatalyst is filtered off, and the solvent is evaporated, leaving 1.3 g.of crude 7-Cl1lOIO-aphenyl-1,2,3,4 tetrahydroisoquinoline-l-methanol asan oil.

When Steps A, B and C immediately above are repeated usingN-(p-methylphenethyl)-2-phenyl acetamide orN-(p-fluorophenethyl)-2-phenyl acetamide in place ofN-(p-chlorophenethyl)-2-phenyl acetamide, there is obtained7-methyl-a-phenyl 1,2,3,4-tetrahydroisoquinoline-- l-methanol (M.P.10l102 C.) or 7-fluoro-a-phenyl-1,2,3,4-tetrahydroisoquinoline-l-methanol, respectively.

What is claimed is: 1. A compound selected from the group consisting ofisoquinolines of the formula and a pharmaceutically acceptable acidaddition salt thereof, wherein R, R R and R independently is hydrogen,trifluoromethyl, or halo having an atomic weight of about 19-36;

R and R independently, is hydrogen, straight chain lower alkyl, or halohaving an atomic weight of about 19-36; and

provided (1) no more than three of R, R R R R and R are other thanhydrogen, and (2) R, R, R and R are such that there is never atrifluoromethyl group on each of two adjacent carbon atoms.

2. The compound of claim 1 which is l-(p-chlorophenyl)-3-imino1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a1isoquinoline.

3. The compound of claim 1 which is 1-phenyl-3-imino- 1,5 ,6, 10b-tetrahydro-3H-oxazolo [4,3 -a] isoquinoline.

4. The compound of claim 1 which isl-(p-fluorophenyl)-3-imino-1,5,6,IOb-tetrahydro3H-oxazolo[4,3-a]isoquinoline.

5. The compound of claim 1 which is l-(m-trifluoron1ethylphenyl)-3-imino1,5,6,10b tetrahydro-3H-oxazolo [4,3-a] isoquinoline.

6. The compound of claim 1 which is 1-(3,4-dichlorophenyl)-3-imino1,5,6,10b-tetrahydro-BH-oxazolo [4,3-a] isoquinoline.

7. The compound of claim 1 which is1-(2,4-dichlorophenyl)-3-imino-1,5,6,10b-tetrahydro 3H oxazolo[4,3- a]isoquinoline.

8. The compound of claim 1 which is 1-phenyl-3-imino-9-methyl-1,5,6,10b-tetrahydro 3H oxazolo[4,3- a]isoquinoline.

9. The compound of claim 1 which is 1-phenyl-3-imino-9-chloro-1,5,6,10btetrahydro 3H oxazolo[4,3- a] isoquinoline.

10. The compound of claim 1 which is 1-phenyl-3-imino-9-fluoro-1,5,6,10b-tetrahydro 3H oxazolo[4,3-a] isoquinoline.

11. The compound of claim 1 which is 1-(p-chlorophenyl)-3-imino-l,5,6,10b-tetrahydro 3H oxazolo[4,3 a]isoquinolinemaleate.

12. A pharmaceutically acceptable acid addition salt of a compound ofthe formula fink s-..

where R, R R and R independently, is hydrogen, trifluoromethyl, or halohaving an atomic weight of about 1936;

R and R independently, is hydrogen, straight chain lower alkyl, or halohaving an atomic weight of about 1936; and

Alk is straight chain lower alkyl,

provided (1) no more than three of R, R R R R and R are other thanhydrogen, and (2) R, R R and R are such that there is never atrifluoromethyl group on each of two adjacent carbon atoms.

13. A compound according to claim 12 which is 1-phenyl-3-imino5-methyl-1,5,6,10b-tetrahydro 3H 0X- azolo [4,3 -a]isoquinoline hydrochloride.

14. A compound according to claim 12 which isl-pchlorophenyl-3-imino-5-methyl-1,5,6,IOb-tetrahydro 3H-oxazolo[4,3-a]isoquinoline hydrobromide.

13 14 15. A compound according to claim 12 which is 1- 3,336,306 8/1967Sulkowski 260289X (3,4-dichl0ropheny1)-3-imino-5-methy1 1,5,6,10b tctra-3,452,010 6/1969 Pohlks et a1. 260-288X hydro-3H-oxazo1o [4,3-a]isoquinoline hydrochloride.

References Cited UNITED STATES PATENTS OTHER REFERENCES Davis: J. Org.Chem, v01. 25, pp. 376-8 as abstracted 5 in Chem. Abstr. vol. 54, col.19676 (1960).

Haa t j -h- 6 DONALD G. DAUS, Primary Examiner Weis ac 260288 Brossi eta1. 260288X Koch 260-288 10 260287, 288, 289, 558; 424258

